The objective of this study is to elucidate those early events in HIV infection that may lead to pathogenesis. Macrophages are infected in the circulatory system as well as in the brain. We have identified the early innate immunological responses following HIV infection of primary human macrophages: induction of the chemokines CXCL8 and CXCL10. CXCL8 recruits neutrophils, which are the hallmark of acute inflammation and can mediate tissue damage;CXCL10, also generated by the HIV-infected macrophage, recruits activated CD4 T cells and more macrophages, which become productively infected by the macrophage HIV particles. This year we have shown that these responses are mediated by independent cellular innate immune response mechanisms, and have identified a macrophage/microglia innate immune receptor that recognizes a yet undefined component of the HIV particle. We have also found that non-HIV retroviruses are unable to induce this signal in macrophages, suggesting that this receptor has specificity for HIV. Recent work by others has shown that this receptor is used by neurons to affect brain development, instead of recognition of a foreign viral component. This suggests that the presence of HIV particles can alter neuron developmental states in the absence of neuron infection by HIV. HIV infection of infants can result in a unique disease with developmental pathology of the brain. Nef is the first gene expressed in newly infected cells, and is central, through an undefined activity, to pathogenesis. This year we have placed Nef molecular activities within a complex of kinases and phosphatases. Finding fundamental cellular activities for this viral protein is likely to help resolve its biochemical role in AIDS development, and understanding the molecular activities of this HIV protein opens potential points of intervention. Future efforts will include identifying the mechanism(s) of CXCL8 and CXCL10 induction by HIV infection of macrophages, and how this might contribute to pathogenesis. We will also continue our exploration of the biochemical activity of the Nef protein.